Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt

Abstract

We have developed a restriction map of the chromosome 21 breakpoint region involved in t(8;21)(q22;q22.3) acute myelogenous leukemia (AML) and have isolated a genomic junction clone containing chromosome 8 and 21 material. Using probes from these regions, rearrangements have been identified in each of nine cases of t(8;21) AML examined. In addition, we have isolated cDNA clones from a t(8;21) AML cDNA library that contain fused sequences from chromosome 8 and 21. The chromosome 8 component, referred to as ETO (for eight twenty-one), is encoded over a large genomic region, as suggested by the analysis of corresponding yeast artificial chromosomes (YACs). The DNA sequence of the chromosome 21 portion of the fusion transcript is derived from the normal AML1 gene. A striking similarity (67% identity over 387 bp, with a corresponding 69% amino acid identity) was detected between AML1 and the Drosophila segmentation gene, runt. The critical consequence of the translocation is the juxtaposition of 5′ sequences of AML1 to 3′ sequences of ETO, oriented telomere to centromere on the der(8) chromosome.

Functional analysis of structural variants in single cells using Strand-seq

“…To deconvolute the effects of driver SVs in patients, we applied scNOVA to analyze the local consequences of balanced SVs, which are widespread in leukemia 3 , 53 . We analyzed primary cells from a patient with acute myeloid leukemia (AML) (32-year-old male; patient-ID = AML_1) bearing a balanced t(8;21) translocation that results in RUNX1-RUNX1T1 gene fusion 54 . We sorted CD34 + cells from AML_1 (Supplementary Fig.…”

TAF1 plays a critical role in AML1-ETO driven leukemogenesis

“…The t(8;21)(q22;q22) is the most commonly observed chromosomal translocation in acute myeloid leukemia (AML) patients; it generates the AML1-ETO (AE) fusion protein 1–4 , which contains the N-terminal 177 amino acids of AML1 [also known as RUNX1 (runt-related transcription factor 1)] fused to nearly the entire ETO protein 1–4 . AE impairs myeloid differentiation and promotes the self-renewal of hematopoietic stem cells (HSCs) 5–7 ; both are critical for AE-driven leukemia development.…”

Myeloid translocation gene 16 is required for maintenance of haematopoietic stem cell quiescence

“…The t(8;21) and t(16;21) target two closely related Myeloid Translocation Gene (MTG) family members, MTG8 (also known as RUNX1T1 or ETO) and MTG16 (also known as CBFA2T3 or ETO2), respectively. The t(8;21) is associated with 12-15% of de-novo acute myeloid leukaemia (AML) cases, while the t(16;21) is more rare and associated with therapy-related AML (Miyoshi et al, 1991;Erickson et al, 1992;Gamou et al, 1998;Davis et al, 1999). Both of these translocations create fusion proteins containing the DNA binding domain of RUNX1 (formerly called AML1) fused to nearly full-length of MTG8 or MTG16 (Miyoshi et al, 1991(Miyoshi et al, , 1993Erickson et al, 1992;Gamou et al, 1998).…”